Figure 1

Genetic testing strategy for Kallmann syndrome. The strategy is based on patient's gender, familial history (if any) and putative mode of disease inheritance, and the presence of additional clinical anomalies that may direct the geneticist towards a particular disease gene or, occasionally, a contiguous gene syndrome at Xp22.3³⁶ or 8p11.2 p12.⁷ The search for KAL1 mutations is restricted to affected males, either isolated cases or patients with a familial history compatible with X-linked recessive mode of inheritance. Mutation screening of the known KS genes (KAL1, FGFR1, FGF8, PROKR2, PROK2) leads to the identification of a mutation in less than one-third of the patients. Notably, as many as 30% of the mutations found in FGFR1 might be de novo mutations, certainly a possibility to be considered before assessing recurrence risk of this genetic form in a family. The main differential diagnoses of KS are normosmic idiopathic hypogonadotropic hypogonadism and CHARGE syndrome.